Epidermal growth factor-induced ovarian carcinoma cell migration is associated with JAK2/STAT3 signals and changes in the abundance and localization of alpha6beta1 integrin.
Peritoneal dissemination of ovarian carcinoma is mediated by epithelial-mesenchymal interconversions leading to the disruption of cell-cell contact and modulation of cell-extracellular matrix (ECM) interactions. The present study was designed to evaluate the effects of epidermal growth factor (EGF) as a modulator of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) signalling and changes in integrin expression during the process similar to EMT. A fibroblastic morphology with reduced intercellular cell contacts and increased cell motility was observed in ovarian cancer cell lines in response to EGF and was concomitant with the up regulation of EMT-associated N-cadherin and vimentin expression. These changes were accompanied by an increase in alpha2, alpha6 and beta1 integrin subunits and activation of JAK2 and STAT3 signalling which was suppressed by a specific JAK2 inhibitor. Consistent with the suppression of STAT3 activity, N-cadherin and vimentin expression were abrogated and was coherent with the loss of cell motility and the expression of alpha6 and beta1 integrin subunits. Neutralizing antibodies against alpha6 and beta1 subunits inhibited cancer cell migration. A strong correlation between the expression of N-cadherin, vimentin and JAK2/STAT3 levels were detected in high-grade ovarian tumors and was consistent with the previously reported enhanced expression of alpha6 integrin subunit in advanced tumors [Ahmed N, Riley C, Oliva K, Rice G, Quinn M. Ascites induces modulation of alpha6beta1 integrin and urokinase plasminogen activator receptor expression and associated functions in ovarian carcinoma. British Journal of Cancer 2005;92:1475-85]. Our data incorporating the clinical samples and the cancer cell lines is the first to demonstrate that JAK2/STAT3 pathway may be one of the downstream events in EMT-like process and alpha6beta1 integrin-mediated signalling in ovarian carcinomas.
Colomiere
Michelle
M
Women's Cancer Research Centre, Royal Women's Hospital, Melbourne, Australia.
Findlay
Jock
J
Ackland
Leigh
L
Ahmed
Nuzhat
N
D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D039121:Integrin alpha6beta1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014746:Vimentin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; D039121:Integrin alpha6beta1; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014746:Vimentin; D004815:Epidermal Growth Factor; D053614:Janus Kinase 2